The consequences of neonatal white matter injury are devastating and represent a major societal problem as currently there is no cure.Prematurity,low weight birth and maternal pre-natal infection are the most frequent...The consequences of neonatal white matter injury are devastating and represent a major societal problem as currently there is no cure.Prematurity,low weight birth and maternal pre-natal infection are the most frequent causes of acquired myelin deficiency in the human neonate leading to cerebral palsy and cognitive impairment.In the developing brain,oligodendrocyte(OL)maturation occurs perinatally,and immature OLs are particularly vulnerable.Cell replacement therapy is often considered a viable option to replace progenitors that die due to glutamate excitotoxicity.We previously reported directed specification and mobilization of endogenous committed and uncommitted neural progenitors by the combination of transferrin and insulin growth factor 1(TSC1).Here,considering cell replacement and integration as therapeutic goals,we examined if OL progenitors(OLPs)grafted into the brain parenchyma of mice that were subjected to an excitotoxic insult could rescue white matter injury.For that purpose,we used a well-established model of glutamate excitotoxic injury.Four-day-old mice received a single intraparenchymal injection of the glutamate receptor agonist N-methyl-D-aspartate alone or in conjunction with TSC1 in the presence or absence of OLPs grafted into the brain parenchyma.Energetics and expression of stress proteins and OL developmental specific markers were examined.A comparison of the proteomic profile per treatment was also ascertained.We found that OLPs did not survive in the excitotoxic environment when grafted alone.In contrast,when combined with TSC1,survival and integration of grafted OLPs was observed.Further,energy metabolism in OLPs was significantly increased by N-methyl-D-aspartate and modulated by TSC1.The proteomic profile after the various treatments showed elevated ubiquitination and stress/heat shock protein 90 in response to N-methyl-D-aspartate.These changes were reversed in the presence of TSC1 and ubiquitination was decreased.The results obtained in this pre-clinical study indicate that the use of a combinatorial intervention including both trophic support and healthy OLPs constitutes a promising approach for long-term survival and successful graft integration.We established optimal conditioning of the host brain environment to promote long-term survival and integration of grafted OLPs into an inflamed neonate host brain.Experimental procedures were performed under the United States Public Health Service Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care Committee at(UCLA)(ARC#1992-034-61)on July 1,2010.展开更多
The negative impact of the term canji ren("handicapped person")has gradually come to be recognized.The terms canzhang ren("person with disabilities")and canji ren("handicapped person")hav...The negative impact of the term canji ren("handicapped person")has gradually come to be recognized.The terms canzhang ren("person with disabilities")and canji ren("handicapped person")have been used interchangeably in academia.However,such interchangeable use causes difficulties for both law enforcement and the judiciary,and also gives rise to public confusion.Based on the etymology of"disabled",its Chinese translation,and a survey of the three models of the concept of"disability",it is apparent that the Convention on the Rights of Persons with Disabilities adopts an"integrated definition"of disability.Law of the People’s Republic of China on the Protection of Disabled Persons defines handicapped person in much the same way as the Convention on the Rights of Persons with Disabilities,with only minor deviations.Hence,to replace the term handicapped person with persons with disabilities is both in line with relevant provisions of the Convention as well as the legislative intent of China’s"Law on the Protection of Disabled Persons".In addition,this benefits the elimination of social discrimination and prejudice,as well as expanding the scope of legal protection.展开更多
Autism, also known as autism, is a kind of brain developmental disorder characterized by social communication disorder, communication disorder and repetitive interest behavior. Autism begins before the age of three an...Autism, also known as autism, is a kind of brain developmental disorder characterized by social communication disorder, communication disorder and repetitive interest behavior. Autism begins before the age of three and manifests itself after the age of three. Most children need long-term rehabilitation training and special education support. In the behavioral function analysis of special children, screaming has not been systematically studied separately from other problematic behaviors such as aggressive behaviors. This functional analysis can help to identify the variables that may maintain screaming, and has certain reference value for children with such problematic behaviors.展开更多
Background:Advanced technology has become a valuable tool in etiological studies of intellectual disability/global developmental delay(ID/GDD).The present study investigated the role of genetic analysis to confirm the...Background:Advanced technology has become a valuable tool in etiological studies of intellectual disability/global developmental delay(ID/GDD).The present study investigated the role of genetic analysis to confirm the etiology in ID/GDD patients where the cause of the disease was uncertain in central China.Methods:We evaluated 1051 ID/GDD children aged 6 months to 18 years from March 2009 to April 2017.Data concerning basic clinical manifestations were collected,and the method of etiology confirmation was recorded.Genome-wide copy number variations(CNVs)detection and high-throughput sequencing of exons in the targeted regions was performed to identify genetically-based etiologies.We compared the incidence of different methods used to confirm ID/GDD etiology among groups with differing degrees of ID/GDD using the Chi-square or Fisher exact probability test.Results:We recruited 1051 children with mild(367,34.9%),moderate(301,28.6%),severe(310,29.5%),and profoundly severe(73,6.9%)ID/GDD.The main causes of ID/GDD in the children assessed were perinatal factors,such as acquired brain injury,as well as single gene imbalance and chromosomal gene mutation.We identified karyotype and/or CNVs variation in 46/96(47.9%)of cases in severe ID/GDD patients,which was significantly higher than those with mild and moderate ID/GDD of 34/96(35.4%)and 15/96(15.6%),respectively.A total of 331/536(61.8%)patients with clear etiology have undergone genetic analysis while 262/515(50.9%)patients with unclear etiology have undergone genetic analysis(x^2=12.645,P<0.001).Gene structure variation via karyotype analysis and CNV detection increased the proportion of children with confirmed etiology from 51.0%to 56.3%,and second-generation high-throughput sequencing dramatically increased this to 78.9%.Ten novel mutations were detected,recessive mutations in X-linked genes(ATPase copper transporting alpha and bromodomain and WD repeat domain containing 3)and dominant de novo heterozygous mutations in X-linked genes(cyclin-dependent kinase like 5,protocadherin 19,IQ motif and Sec7 domain 2,and methyl-CpG binding protein 2)were reported in the study.Conclusions:The present study indicates that genetic analysis is an effective method to increase the proportion of confirmed etiology in ID/GDD children and is highly recommended,especially in ID/GDD children with uncertain etiology.展开更多
Aging associated cognitive decline has been linked to dampened neural stem/progenitor cells （NSC/NPCs） activities manifested by decreased proliferation, reduced propensity to produce neurons, and increased different...Aging associated cognitive decline has been linked to dampened neural stem/progenitor cells （NSC/NPCs） activities manifested by decreased proliferation, reduced propensity to produce neurons, and increased differentiation into astrocytes. While gene transcription changes objectively reveal molecular alterations of cells undergoing various biological processes, the search for molecular mechanisms underlying aging of NSC/NPCs has been confronted by the enormous heterogeneity in cellular compositions of the brain and the complex cellular microenvironment where NSC/NPCs reside. Moreover, brain NSClNPCs themselves are not a homogenous population, making it even more difficult to uncover NSC/NPC sub-type specific aging mechanisms. Here, using both population-based and single cell transcriptome analyses of young and aged mouse forebrain ependymal and subependymal regions and comprehensive ＂big-data＂ processing, we report that NSCINPCs reside in a rather inflammatory environment in aged brain, which likely contributes to the differentiation bias towards astrocytes versus neurons. Moreover, single cell transcriptome analyses revealed that different aged NSCINPC subpopulations, while all have reduced cell proliferation, use different gene transcription programs to regulate age-dependent decline in cell cycle. Inter- estingly, changes in cell proliferation capacity are not influenced by inflammatory cytokines, but likely result from cell intrinsic mechanisms. The ErkJMapk pathway appears to be critically involved in regulating age-dependent changes in the capacity for NSCINPCs to undergo clonal expansion. Together this study is the first example of using population and single cell based transcriptome analyses to unveil the molecular interplay between different NSCINPCs and their microenvironment in the context of the aging brain.展开更多
To the Editor:Currently,there is no standardized treatment protocol for the pediatric anti-N-methyl-D-aspartate receptor(NMDAR).There are two surveys by Kahn et al[1]and Bartolini et al[2]that aimed at determining the...To the Editor:Currently,there is no standardized treatment protocol for the pediatric anti-N-methyl-D-aspartate receptor(NMDAR).There are two surveys by Kahn et al[1]and Bartolini et al[2]that aimed at determining the treatment strategies that are used for pediatric NMDAR encephalitis in other parts of the world rather than China.Bartolini et al[2]performed a worldwide survey involving 199 participants:61 adult neurologists,86 pediatric neurologists,and 52 pediatric rheumatologists.Their survey investigated the differences in anti-NMDAR encephalitis treatment strategies,according to medical specialty,years in practice,and geographical location.[2]The survey of Kahn et al[1]involved 151 pediatric neurologists and focused on identifying the indications for the initiation of immunotherapy,type of the used immunotherapy,length of the first-line immunotherapy,time for the initiation of the second-line immunotherapy,and the preferable options for the second-line immunotherapy.Additionally,they investigated the indications and time for adding a disease-modifying therapy,and how long should patients continue with the immunotherapy once returned to their neurologic baseline.[1]Both surveys did not sufficiently focus on identifying the utility of the modified Rankin Scale(mRS),dosages and duration of the treatments(including the duration of oral prednisone),the utility of Cluster of Differentiation 19 positive(CD19+)B cells in adjusting the dosages of rituximab,the necessity of long-term immunosuppressive treatment(for relapse prevention),and the indications for stopping the immunotherapy.展开更多
There is lack of prospective evidence regarding vagal nerve stimulator(VNS)in younger children with intractable epilepsy.Here,we report the outcomes of using VNS in two pre-school patients for pediatric intractable ep...There is lack of prospective evidence regarding vagal nerve stimulator(VNS)in younger children with intractable epilepsy.Here,we report the outcomes of using VNS in two pre-school patients for pediatric intractable epilepsy(VNS-PIE)study.Medical treatment was ineffective in both the patients,and they underwent VNS implantation.Seizure frequency,score on the Gesell scale,and heart rate variability(HRV)were assessed following VNS therapy.After 6 months VNS treatment,the seizure frequency in the two patients decreased by 50%from that at baseline,based on the records in their epileptic diary.Video electroencephalography(EEG)examinations showed that abnormal fast waves diminished in the background in Patient 1,and captured seizure frequency in Patient 2 remarkably decreased.The adaptability,language,and individual and social interaction on their Gesell scales increased slightly,suggesting that VNS had a positive effect on the development of these two children.Moreover,the changes in the different HRV indices indicated improved cardiac autonomic function.In conclusion,these two cases indicated that VNS may not only be a superior therapy for pre-school children with intractable epilepsy,but also may exert a positive effect on their mental development and cardiac autonomic function.展开更多
基金The Cell Culture Core supported by grant No.PP1498:Neural Cell Culture Core and NIH grant No.04612 Intellectual&Developmental Disabilities.The Cell,Circuits and Systems Analysis Core is supported by NICHD award No.U54HD087101-03
文摘The consequences of neonatal white matter injury are devastating and represent a major societal problem as currently there is no cure.Prematurity,low weight birth and maternal pre-natal infection are the most frequent causes of acquired myelin deficiency in the human neonate leading to cerebral palsy and cognitive impairment.In the developing brain,oligodendrocyte(OL)maturation occurs perinatally,and immature OLs are particularly vulnerable.Cell replacement therapy is often considered a viable option to replace progenitors that die due to glutamate excitotoxicity.We previously reported directed specification and mobilization of endogenous committed and uncommitted neural progenitors by the combination of transferrin and insulin growth factor 1(TSC1).Here,considering cell replacement and integration as therapeutic goals,we examined if OL progenitors(OLPs)grafted into the brain parenchyma of mice that were subjected to an excitotoxic insult could rescue white matter injury.For that purpose,we used a well-established model of glutamate excitotoxic injury.Four-day-old mice received a single intraparenchymal injection of the glutamate receptor agonist N-methyl-D-aspartate alone or in conjunction with TSC1 in the presence or absence of OLPs grafted into the brain parenchyma.Energetics and expression of stress proteins and OL developmental specific markers were examined.A comparison of the proteomic profile per treatment was also ascertained.We found that OLPs did not survive in the excitotoxic environment when grafted alone.In contrast,when combined with TSC1,survival and integration of grafted OLPs was observed.Further,energy metabolism in OLPs was significantly increased by N-methyl-D-aspartate and modulated by TSC1.The proteomic profile after the various treatments showed elevated ubiquitination and stress/heat shock protein 90 in response to N-methyl-D-aspartate.These changes were reversed in the presence of TSC1 and ubiquitination was decreased.The results obtained in this pre-clinical study indicate that the use of a combinatorial intervention including both trophic support and healthy OLPs constitutes a promising approach for long-term survival and successful graft integration.We established optimal conditioning of the host brain environment to promote long-term survival and integration of grafted OLPs into an inflamed neonate host brain.Experimental procedures were performed under the United States Public Health Service Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care Committee at(UCLA)(ARC#1992-034-61)on July 1,2010.
基金one of the phased achievements of“Research on the Design and Policy Intervention Mechanism of the Protection System for Persons with Disabilities’Right to Education in Western Rural Areas”,a fund of the Ministry of Education in 2016 to support young scholars in humanities and social sciences(16YJC880049).
文摘The negative impact of the term canji ren("handicapped person")has gradually come to be recognized.The terms canzhang ren("person with disabilities")and canji ren("handicapped person")have been used interchangeably in academia.However,such interchangeable use causes difficulties for both law enforcement and the judiciary,and also gives rise to public confusion.Based on the etymology of"disabled",its Chinese translation,and a survey of the three models of the concept of"disability",it is apparent that the Convention on the Rights of Persons with Disabilities adopts an"integrated definition"of disability.Law of the People’s Republic of China on the Protection of Disabled Persons defines handicapped person in much the same way as the Convention on the Rights of Persons with Disabilities,with only minor deviations.Hence,to replace the term handicapped person with persons with disabilities is both in line with relevant provisions of the Convention as well as the legislative intent of China’s"Law on the Protection of Disabled Persons".In addition,this benefits the elimination of social discrimination and prejudice,as well as expanding the scope of legal protection.
文摘Autism, also known as autism, is a kind of brain developmental disorder characterized by social communication disorder, communication disorder and repetitive interest behavior. Autism begins before the age of three and manifests itself after the age of three. Most children need long-term rehabilitation training and special education support. In the behavioral function analysis of special children, screaming has not been systematically studied separately from other problematic behaviors such as aggressive behaviors. This functional analysis can help to identify the variables that may maintain screaming, and has certain reference value for children with such problematic behaviors.
基金This work was supported by grants from the National Natural Science Foundation of China(No.81771408,No.81771409,and No.81300555)the National Key Research and Development Program of China(No.2016YFC1306202).
文摘Background:Advanced technology has become a valuable tool in etiological studies of intellectual disability/global developmental delay(ID/GDD).The present study investigated the role of genetic analysis to confirm the etiology in ID/GDD patients where the cause of the disease was uncertain in central China.Methods:We evaluated 1051 ID/GDD children aged 6 months to 18 years from March 2009 to April 2017.Data concerning basic clinical manifestations were collected,and the method of etiology confirmation was recorded.Genome-wide copy number variations(CNVs)detection and high-throughput sequencing of exons in the targeted regions was performed to identify genetically-based etiologies.We compared the incidence of different methods used to confirm ID/GDD etiology among groups with differing degrees of ID/GDD using the Chi-square or Fisher exact probability test.Results:We recruited 1051 children with mild(367,34.9%),moderate(301,28.6%),severe(310,29.5%),and profoundly severe(73,6.9%)ID/GDD.The main causes of ID/GDD in the children assessed were perinatal factors,such as acquired brain injury,as well as single gene imbalance and chromosomal gene mutation.We identified karyotype and/or CNVs variation in 46/96(47.9%)of cases in severe ID/GDD patients,which was significantly higher than those with mild and moderate ID/GDD of 34/96(35.4%)and 15/96(15.6%),respectively.A total of 331/536(61.8%)patients with clear etiology have undergone genetic analysis while 262/515(50.9%)patients with unclear etiology have undergone genetic analysis(x^2=12.645,P<0.001).Gene structure variation via karyotype analysis and CNV detection increased the proportion of children with confirmed etiology from 51.0%to 56.3%,and second-generation high-throughput sequencing dramatically increased this to 78.9%.Ten novel mutations were detected,recessive mutations in X-linked genes(ATPase copper transporting alpha and bromodomain and WD repeat domain containing 3)and dominant de novo heterozygous mutations in X-linked genes(cyclin-dependent kinase like 5,protocadherin 19,IQ motif and Sec7 domain 2,and methyl-CpG binding protein 2)were reported in the study.Conclusions:The present study indicates that genetic analysis is an effective method to increase the proportion of confirmed etiology in ID/GDD children and is highly recommended,especially in ID/GDD children with uncertain etiology.
基金This study was supported by China National Key Research and Development Program （2016YFA0100801 YS）, and the National Natural Science Foundation of China （Grant Nos. 8133030 YS and 31620103904 YS）, and grants： 2016YFC102705 YS 2014BAI04B07 WZL+1 种基金 81470715 YSTJ1504219036 WZL.
文摘Aging associated cognitive decline has been linked to dampened neural stem/progenitor cells （NSC/NPCs） activities manifested by decreased proliferation, reduced propensity to produce neurons, and increased differentiation into astrocytes. While gene transcription changes objectively reveal molecular alterations of cells undergoing various biological processes, the search for molecular mechanisms underlying aging of NSC/NPCs has been confronted by the enormous heterogeneity in cellular compositions of the brain and the complex cellular microenvironment where NSC/NPCs reside. Moreover, brain NSClNPCs themselves are not a homogenous population, making it even more difficult to uncover NSC/NPC sub-type specific aging mechanisms. Here, using both population-based and single cell transcriptome analyses of young and aged mouse forebrain ependymal and subependymal regions and comprehensive ＂big-data＂ processing, we report that NSCINPCs reside in a rather inflammatory environment in aged brain, which likely contributes to the differentiation bias towards astrocytes versus neurons. Moreover, single cell transcriptome analyses revealed that different aged NSCINPC subpopulations, while all have reduced cell proliferation, use different gene transcription programs to regulate age-dependent decline in cell cycle. Inter- estingly, changes in cell proliferation capacity are not influenced by inflammatory cytokines, but likely result from cell intrinsic mechanisms. The ErkJMapk pathway appears to be critically involved in regulating age-dependent changes in the capacity for NSCINPCs to undergo clonal expansion. Together this study is the first example of using population and single cell based transcriptome analyses to unveil the molecular interplay between different NSCINPCs and their microenvironment in the context of the aging brain.
文摘To the Editor:Currently,there is no standardized treatment protocol for the pediatric anti-N-methyl-D-aspartate receptor(NMDAR).There are two surveys by Kahn et al[1]and Bartolini et al[2]that aimed at determining the treatment strategies that are used for pediatric NMDAR encephalitis in other parts of the world rather than China.Bartolini et al[2]performed a worldwide survey involving 199 participants:61 adult neurologists,86 pediatric neurologists,and 52 pediatric rheumatologists.Their survey investigated the differences in anti-NMDAR encephalitis treatment strategies,according to medical specialty,years in practice,and geographical location.[2]The survey of Kahn et al[1]involved 151 pediatric neurologists and focused on identifying the indications for the initiation of immunotherapy,type of the used immunotherapy,length of the first-line immunotherapy,time for the initiation of the second-line immunotherapy,and the preferable options for the second-line immunotherapy.Additionally,they investigated the indications and time for adding a disease-modifying therapy,and how long should patients continue with the immunotherapy once returned to their neurologic baseline.[1]Both surveys did not sufficiently focus on identifying the utility of the modified Rankin Scale(mRS),dosages and duration of the treatments(including the duration of oral prednisone),the utility of Cluster of Differentiation 19 positive(CD19+)B cells in adjusting the dosages of rituximab,the necessity of long-term immunosuppressive treatment(for relapse prevention),and the indications for stopping the immunotherapy.
基金supported by the following fundings:The National Key Research and Development Program of China(Grant No.2016YFC0105502)National Natural Science Foundation of China(NSFC+1 种基金Grant No.81527901)Shenzhen International Cooperative Research Project(Grant No.GJHZ20180930110402104).
文摘There is lack of prospective evidence regarding vagal nerve stimulator(VNS)in younger children with intractable epilepsy.Here,we report the outcomes of using VNS in two pre-school patients for pediatric intractable epilepsy(VNS-PIE)study.Medical treatment was ineffective in both the patients,and they underwent VNS implantation.Seizure frequency,score on the Gesell scale,and heart rate variability(HRV)were assessed following VNS therapy.After 6 months VNS treatment,the seizure frequency in the two patients decreased by 50%from that at baseline,based on the records in their epileptic diary.Video electroencephalography(EEG)examinations showed that abnormal fast waves diminished in the background in Patient 1,and captured seizure frequency in Patient 2 remarkably decreased.The adaptability,language,and individual and social interaction on their Gesell scales increased slightly,suggesting that VNS had a positive effect on the development of these two children.Moreover,the changes in the different HRV indices indicated improved cardiac autonomic function.In conclusion,these two cases indicated that VNS may not only be a superior therapy for pre-school children with intractable epilepsy,but also may exert a positive effect on their mental development and cardiac autonomic function.
